Implant with fillable reservoir

ABSTRACT

Implants with fillable reservoirs have been developed that are suitable for rhinoplasty, breast reconstruction, ear reconstruction, and replacement, reconstruction or repair of other soft tissues. The implants can be filled with graft material prior to implantation. The implants are preferably made from resorbable polymers, can be tailored to provide different geometries, mechanical properties and resorption rates in order to provide more consistent surgical outcomes. The implants preferably have an interconnected network of unit cells with rnicroporous outer layers and optionally some or all of the unit cells having at least one macropore in their outer layers. The implants can be loaded by injection with microfat, collagen, DCF, cells, bioactive agents, and other augmentation materials, prior to implantation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication No. 62/587,859, filed Nov. 17, 2017, which is herebyincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to the field of surgery, andmore particularly, the invention relates to implants with reservoirsthat can be filled with augmentation material, such as fat, microfat,collagen, gels, hydrogels, and bioactive agents. The reservoir of theimplant comprises a microporous outer layer and either an interconnectednetwork of unit, cells, or the edges of the microporous outer layer havebeen sealed. The reservoir can be filled with graft material andbioactive agents prior to implantation or post-implantation. The implantmay optionally comprise macroporous fiber structure inside the finablereservoir, and may also optionally comprise one or more macropores inthe outer microporous layer. The implants are suitable for use wherespace filling is required in the human anatomy, in particularrhinoplasty, ear, facial and breast reconstruction.

BACKGROUND OF THE INVENTION

Rhinoplasty is a complex procedure requiring the alteration ofunderlying nasal structures such as bone, cartilage, ligaments and softtissue. It may be undertaken for a variety of reasons, including (i)improving aesthetic appearance of the patient's nose; (ii) restoringstructure and shape following trauma; (iii) correcting abnormalities ofthe nose; and (iv) correcting functional problems of the nasal passageto improve breathing. Regardless of the reasons for rhinoplasty, thesurgeon seeks to create or preserve certain proportions between variousparts of the nose and face in order to restore or maintainfunctionality, remediate structural issues, and address aestheticfactors.

Augmentation of the nasal dorsum, to build up the bridge of the nose, isa common rhinoplasty procedure used to treat patients with collapsed orflat noses, or to change the appearance of a relatively low bridge,common in certain ethnic groups, to a more projected, pronounced, or“Western” profile,

One preferred method to augment the dorsum involves the use of dicedcartilage fascia (DCF). The use of DCF is often preferred to solidgrafts of autologous costal cartilage because the solid grafts can warp,and also because they have limited availability when long, straightgrafts are needed. In contrast, DCF may be obtained, for example, fromcartilage of the rib, ear, or septum. The cartilage is chopped into verysmall pieces, typically about 0.5 to 1 mm cubes. Rib cartilage is aparticularly abundant source of autologous cartilage graft material. Toaugment the dorsum, the DCF is placed inside a small pouch made from anautologous fascia (commonly temporalis fascia), the pouch is manuallysealed using sutures, and inserted onto the dorsum by the surgeon. Thisapproach provides greater flexibility in shape and size, and reduces therisk of warping when compared to solid grafts. The use of a pouchmaterial for the DCF prevents uncontrolled dispersion of the cartilagefragments, reduces palpability and improves appearance (relative to useof DCF without a pouch).

Materials that have been used to form a pouch for DCF include Surgicel®(Ethicon, San Lorenzo), an oxidized regenerated cellulose hemostat,AltoDean® (LifeCell, Bridgewater), an acellular tissue allograft derivedfrom cadaver skin, and deep temporal fascia autograft. However, each ofthese materials has their challenges. The Surgicel and AlloDerm productshave been associated with cartilage resorption, and the use of temporalfascia, harvested from tissue in the temple region of the head, resultsin increased operating time, and produces morbidity at a second surgicalsite. It has also been reported that temporal fascia can lackconsistency, has a tendency to shrink, has poor dimensional stability,and that harvesting of temporal fascia can create the risk of alopecia.Moreover, it is not possible to easily control the degradation rate,three-dimensional geometry, or thickness of harvested tissues, orincorporate bioactive agents into harvested tissues. Therefore, there isstill a need for improved rhinoplasty implants.

An implant for use in rhinoplasty, particularly a reservoir that can befilled with microfat, fat, fat extracts, cells, gels, hydrogels, orother biological material, that does not need to be harvested from thepatient and that can be engineered with a desired thickness and shape,including three-dimensional shapes, would be particularly desirable. Forexample, an implant that could be formed in a range of sizes, includingdifferent thicknesses, to address palpability issues and other facialcontouring needs would be very desirable. Preferably, the implant isable to act as a wick to take up, for example, microfat, fat, fatextracts, cells, stem cells, collagen, and other biological materials,and help prevent loss of these materials from the implant. It would alsobe highly desirable for the implant to allow tissue-ingrowth,particularly when the thickness of the implant is greater than 1 mm, andfor the implant to have a tunable rate of degradation leading tocomplete degradation. Ideally, it would also be desirable for theimplant to comprise bioactive agents, including, but not limited to,growth factors and antibiotics that can improve the performance of theimplant and the surgical outcome. It would also be desirable if theimplant could be used in other procedures, such as ear reconstructionand breast augmentation and reconstruction, as well as the repair orreconstruction of soft tissue.

It is therefore an object of the invention to provide an implant with atillable reservoir.

It is another object of the invention to provide an implant with afillable reservoir that can be filled with microfat, fat extracts, fat,cells, diced cartilage, DCF, gels, hydrogels, and other bioactive agentsand materials.

It is still another object of the invention to provide an implant with atillable reservoir, wherein the implant allows tissue ingrowth and isresorbable.

It is yet another object of the invention to provide an implant with afillable reservoir, wherein the shape and size of the implant can beengineered, and the implant can be cut and shaped.

It is a still further object of the invention to provide methods to fillthe implant, and methods to use the implant in rhinoplasty, ear andbreast reconstruction, and other soft tissue implantation andaugmentation procedures.

SUMMARY OF THE INVENTION

Implants with a finable reservoir have been developed that are suitablefor use in rhinoplasty, ear and breast reconstruction, and repair,reconstruction, or replacement of other soft tissues. The implantseliminate the need to harvest temporalis fascia, transverse rectusabdominis myocutaneous (TRAM) tissue, or other tissues that are used tomake graft material or pouches, and inconsistencies associated with theuse of harvested biological tissues. The fillable reservoir is made froman outer microporous layer with either an interconnected network of unitcells or by sealing the edges of the microporous layer, wherein theimplant may optionally have at least one macropore. The implants mayfurther comprise macroporous fiber structure inside the implant, and mayalso further comprise additional microporous layers within the implant.The reservoir may be filled with grafting material, such as microfat,fat, fat extracts, cells, stem cells, collagen, DCF, gels, hydrogels,bioactive agents, and other substances useful in rhinoplasty and otherreconstruction or repair procedures. Preferably, the microporous layersare made from polymers and engineered to act as wicks that can take upand retain graft materials, such as microfat, fat extracts, and othersubstances useful in rhinoplasty and other reconstructive procedures.The polymers are preferably degradable with a tunable rate ofdegradation, and are designed to allow tissue in-growth.

Also disclosed is a method of filling the reservoirs of the implantsprior to implantation. The method includes filling the reservoir of theimplant using a.

needle and syringe. The implants can be filled, for example, withmicrofat, fat, fat extracts, cells, stem cells, gels, hydrogels, DCF,fascia, dermis, cartilage, and other substances useful in rhinoplasty,breast and ear reconstruction, and other soft tissue repair andreconstruction procedures. Methods to implant the implants are alsodisclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing isometric and cross-sectional views of animplant that comprises an outer microporous layer with sealed edges, anda finable reservoir. The diagram shows the location where fiber forminga macroporous structure may be placed.

FIG. 2 is a diagram showing isometric and cross-sectional views of animplant that comprises multiple fillable reservoirs made by sealingtogether the edges of multiple microfibrous layers stacked on top ofeach other.

FIG. 3 shows isometric and cross-sectional views of an implant preparedby wrapping a microporous layer around a flat substrate that is mountedon a mandrel. The cross-sectional view shows the reservoir formedbetween the microporous layers, and sealing of the outer edge.

FIG. 4 is a diagram showing cross-sectional, isometric and (op views ofan implant that comprises multiple microporous layers with macroporesvisible in the outermost layer.

FIG. 5 is a diagram showing isometric and cross-sectional views of arhinoplasty implant that comprises finable reservoirs formed byalternating layers of microporous nonwoven and fibers formingmacroporous structure.

FIG. 6 is a diagram showing the use of an engraved calender roll and asmooth calender roll to thermally point-bond an implant.

FIG. 7 is a diagram showing the cross-section of a thermally-bondedfillable reservoir of an implant that is part of an interconnectednetwork of unit cells comprising a microporous outer layer and amacroporous inner layer formed from fibers.

FIG. 8 is a diagram showing the manufacture of a thermally point-bondedimplant with an outer microporous nonwoven layer and an innermacroporous layer of fibers. Area “A” is shown in more detail in FIG. 7.

FIG. 9 is a diagram showing an isometric view, a top view and across-section view of a thermally point-bonded implant with a fillablereservoir made from a network of interconnected unit cells whichoptionally contain loose fiber forming a macroporous structure. Theouter layer of the implant is made from a microporous nonwoven.

FIG. 10 is a diagram showing a pattern of thermal bonding points, and aunit cell created by thermal bonding, that can be used to prepare animplant with a finable reservoir.

FIG. 11 shows pictures of (a) thermal pointed-bonded P4HB implant with atillable reservoir made from dry spun and spun laid fibers, (b) amagnification of picture 11(a) showing the square design of the bondpoints of the thermally point-bonded implant, and (c) a 1.5 cm×3.5 cmrhinoplasty implant that has been filled with 0.8 cc of human microfat.

FIG. 12 is a diagram showing a suitable equipment set up for preparingmelt-blow P4HB.

FIG. 13 shows views of an implant, suitable for use as a meniscus plug,that comprises an outer microporous layer and a tillable reservoircontaining macroporous material. The diagram shows the locations wherethe microporous and macroporous layers have been bonded together to formbarrel-like reservoirs that may be filled, for example, with dicedcartilage.

DETAILED DESCRIPTION OF THE INVENTION

It would be desirable to have a rhinoplasty implant that the surgeon canuse to create or restore certain proportions between various parts ofthe nose and face in order to restore or maintain functionality,remediate structural issues, and address aesthetic factors. Ideally, theimplant can be engineered with a desired shape, and constructed tominimize the need to harvest tissues from the patient which can resultin morbidity at the donor site as well as increase operating time.Furthermore, it would be highly desirable for the implant to permittissue in-growth, degrade in a controlled manner, and be replaced overtime with the patient's own tissue. The use of an implant with atillable reservoir, made from an interconnected network of unit cellscomprising microporous outer layers with some or all of the cells havingat least one macropore, could however allow the surgeon to implant anydesired shape, optionally containing graft or other materials,preferably autologous graft, and permit the implant to be replaced withthe patient's own tissues if the implant is made of resorbablematerials. The implant would preferably be formable or moldable by handinto a desired shape, minimize the need to harvest tissues from thepatient, and provide the surgeon with a desirable means to delivermicrofat, fat, fat extracts, cells, stem cells, gels, hydrogels,bioactive agents, and other material, to the implant site. If desired,the surgeon could cut the implant to further customize the shape andsize of the implant. And, the implant could be used not only inrhinoplasty procedures, but also in other plastic surgery procedures,such as ear and breast reconstruction [for example, as a TRAM(transverse rectus abdominis myocutaneous) flap substitute], and othersoft tissue repair, reconstruction, and replacement procedures.

I. Definitions

“Absorbable” as generally used herein means the material is degraded inthe body, and the degradation products are eliminated or excreted fromthe body. The terms “absorbable”, “resorbable”, “degradable”, and“erodible”, with or without the prefix “bio”, can be usedinterchangeably herein, to describe materials broken down and graduallyabsorbed, excreted, or eliminated by the body, whether degradation isdue mainly to hydrolysis or mediated by metabolic processes. “Averagepore size diameter” as used herein. is calculated using open sourceImageJ software available at https://imagej.nih.gov/ij/index.html.

“Bioactive agent” is used herein to refer to therapeutic, prophylacticor diagnostic agents, preferably agents that promote healing and theregeneration of host tissue, and also therapeutic agents that prevent,inhibit or eliminate infection. “Agent” includes a single such agent andis also intended to include a plurality.

“Biocompatible” as generally used herein means the biological responseto the material or device being appropriate for the device's intendedapplication in vivo. Any metabolites of these materials should also bebiocompatible.

“Blend” as generally used herein means a physical combination ofdifferent polymers, as opposed to a copolymer formed of two or moredifferent monomers.

“Copolymers of poly-4-hydroxybutyrate” as generally used herein meansany polymer containing 4-hydroxybutyrate with one or more differenthydroxy acid units.

“Diced cartilage fascia” (“DCF”) as generally used herein meanscartilage obtained, for example, from the rib, ear, or septum, that hasbeen chopped into very small pieces.

“Elongation to break” as used herein means the increase in length of amaterial that occurs when tension is applied to break the material. Itis expressed as a percentage of the material's original length.

“Endotoxin units” as used herein are determined using the limulusamebocyte lysate (LAL) assay as further described by Gorbet et al.Biomaterials, 26:6811-6817 (2005).

“Macroporous” materials or structures as used herein have average poresize diameters of at least 75 microns.

“Microfat” as generally used herein means fat obtained from an area ofthe body, including the abdomen, thighs, buttocks or waist area, usuallyby making a small incision and using a small cannula to suction it fromthe body, and processed to remove blood cells and reduce the liquidcontent of the aspirate.

“Microporous” materials or structures as generally used herein haveaverage pore size diameters of less than 10 microns.

“Molecular weight” as used herein, unless otherwise specified, refers tothe weight average molecular weight (Mw), not the number averagemolecular weight (Mn), and is measured by GPC relative to polystyrene.

“Poly-4-hydroxybutyrate” as generally used herein means a homopolymercontaining 4-hydroxybutyrate units. It can be referred to herein asTepha's P4HB™ polymer or TephaFLEX® biomaterial (manufactured by Tepha,Inc., Lexington, Mass.).

“Suture pullout strength” as used herein means the peak load (kg) atwhich an implant fails to retain a suture. It is determined using atensile testing machine by securing an implant in a horizontal plate,threading a suture in a loop through the implant at a distance of 1 cmfrom the edge of the implant, and securing the suture arms in a fibergrip positioned above the implant. Testing is performed at a crossheadrate of 100 mm/min, and the peak load (kg) is recorded. The suture isselected so that the implant will fail before the suture fails. Thesuture pullout strength may be converted and expressed as Newtons.

“Unit cell” as generally used herein means a small compartment. Anexample of a unit cell cross-section is shown in FIG. 7 . Thecompartment may be empty or contain a filler.

II. Materials for Preparing Implants with Fillable Reservoirs

Implants with finable reservoirs have been developed. The implants canoptionally be filled with augmentation materials such as microfat, fat,fat extracts, collagen, gels, hydrogels, DCF, cells, stem cells, as wellas bioactive agents, prior to implantation. The shapes and sizes of theimplants can be tailored to meet the individual needs of the patient,and the implants can allow tissue in-growth and preferably are made ofdegradable polymers with a tunable rate of degradation. The implants soformed preferably have a pyrogen level of less than 20 endotoxin unitsper device.

A. Polymers for Preparing Implants with Finable Reservoirs

The implants with finable reservoirs may comprise permanent materials,such as non-degradable thermoplastic polymers, including polymers andcopolymers of ethylene and propylene, including ultra-high molecularweight polyethylene, ultra-high molecular weight polypropylene, nylon,polyesters such as polyethylene terephthalate),poly(tetrafluoroethylene), polyurethanes, poly(ether-urethanes),poly(methylmethacrylate), polyether ether ketone, polyolefins, andpolyethylene oxide). However, the implants preferably comprisedegradable materials, and more preferably are made completely fromdegradable materials. In a preferred embodiment, the implants are madefrom one or more absorbable polymers, preferably absorbablethermoplastic polymers and copolymers. The implant may, for example, beprepared from polymers including, but not limited to, polymers ofglycolic acid, lactic acid, 1,4-dioxanone, trimethylene carbonate,3-hydroxybutyric acid, 4-hydroxybutyrate, ϵ-caprolactone, includingpolyglycolic acid, polylactic acid, polydioxanone, polycaprolactone,copolymers of glycolic and lactic acids, such as VICRYl® polymer, MAXON®and MONOCRYL® polymers, and including poly(lactide-co-caprolactones);poly(orthoesters); polyanhydrides; poly(phosphazenes);polyhydroxyalkanoates; synthetically or biologically preparedpolyesters; polycarbonates; tyrosine polycarbonates; polyamides(including synthetic and natural polyamides, polypeptides, andpoly(amino acids)); polyesteramides; poly(alkylene alkylates);polyethers (such as polyethylene glycol, PEG, and polyethylene oxide,PEO); polyvinyl pyrrolidones or PVP; polyurethanes; polyetheresters;polyacetals; polycyanoacrylates; poly(oxyethylene)/poly(oxypropylene)copolymers; polyacetals, polyketals; polyphosphates;(phosphorous-containing) polymers; polyphosphoesters; polyalkyleneoxalates; polyalkylene succinates; poly(maleic acids); silk (includingrecombinant silks and silk derivatives and analogs); chitin; chitosan;modified chitosan; biocompatible polysaccharides; hydrophilic or watersoluble polymers, such as polyethylene glycol, (PEG) or polyvinylpyrrolidone (PVP), with blocks of other biocompatible or biodegradablepolymers, for example, poly(lactide), poly(lactide-co-glycolide, orpolycaprolcatone and copolymers thereof, including random copolymers andblock copolymers thereof. Preferably the absorbable polymer or copolymerwill be substantially resorbed after implantation within a 1 to 24-monthtimeframe, and retain some residual strength for at least 2 weeks to 2months.

Blends of polymers, preferably absorbable polymers, can also be used toprepare the rhinoplasty implants. Particularly preferred blends ofabsorbable polymers are prepared from absorbable polymers including, butnot limited to, polymers of glycolic acid, lactic acid, 1,4-dioxanone,trimethylene carbonate, 3-hydroxybutyric acid, 4-hydroxybutyrate,ϵ-caprolactone or copolymers thereof.

In a particularly preferred embodiment, poly-4-hydroxybutyrate (Tepha'sP4HB™ polymer, Lexington, Mass.) or a copolymer thereof is used to makethe implant. Copolymers include P4HB with another hydroxyacid, such as3-hydroxybutyrate, and NUB with glycolic acid or lactic acid monomer.Poly-4-hydroxybutyrate is a strong, pliable thermoplastic polyester thatis biocompatible and resorbable (Williams, et al. Poly-4-hydroxybutyrate(P4HB): a new generation of resorbable medical devices for tissue repairand regeneration, Biomed. Tech. 58(5):439-452 (2013)). Uponimplantation, P4HB hydrolyzes to its monomer, and the monomer ismetabolized via the Krebs cycle to carbon dioxide and water. In apreferred embodiment, the P4HB homopolymer and copolymers thereof have aweight average molecular weight, Mw, within the range of 50 kDa to 1,200kDa (by GPC relative to polystyrene) and more preferably from 100 kDa to600 kDa. A weight average molecular weight of the polymer of 50 kDa orhigher is preferred for processing and mechanical properties.

B. Additives

Certain additives may be incorporated into the implant, preferably inthe absorbable polymer, copolymer or blends thereof that are used tomake the implant. Preferably, these additives are incorporated during acompounding process to produce pellets that can be subsequentlymelt-processed. For example, pellets may be extruded into fiberssuitable for making the implants. In another embodiment, the additivesmay be incorporated using a solution-based process, for example, fibersmay be spun from solutions of the polymer and one or more additives. Ina preferred embodiment, the additives are biocompatible, and even morepreferably the additives are both biocompatible and resorbable.

In one embodiment, the additives may be nucleating agents and/orplasticizers. These additives may be added in sufficient quantity toproduce the desired result. In general, these additives may be added inamounts between 1% and 20% by weight. Nucleating agents may beincorporated to increase the rate of crystallization of the polymer,copolymer or blend. Such agents may be used, for example, to facilitatefabrication of the implant, and to improve the mechanical properties ofthe implant. Preferred nucleating agents include, but are not limitedto, salts of organic acids such as calcium citrate, polymers oroligomers of PHA polymers and copolymers, high melting polymers such asPGA, talc, micronized mica, calcium carbonate, ammonium chloride, andaromatic amino acids such as tyrosine and phenylalanine.

Plasticizers that may be incorporated into the compositions forpreparing the implants include, but are not limited to, di-n-butylmaleate, methyl laureate, dibutyl fumarate, di(2-ethylhexyl) (dioctyl)maleate, paraffin, dodecanol, olive oil, soybean oil, polytetramethyleneglycols, methyl oleate, n-propyl oleate, tetrahydofurfuryl oleate,epoxidized linseed oil, 2-ethyl hexyl epoxytallate, glycerol triacetate,methyl linoleate, dibutyl fumarate, methyl acetyl ricinoleate, acetyltri(n-butyl) citrate, acetyl triethyl citrate, tri(n-butyl) citrate,triethyl citrate, bis(2-hydroxyethyl) dimerate, butyl ricinoleate,glyceryl tri-(acetyl ricinoleate), methyl ricinoleate, n-butyl acetylrincinoleate, propylene glycol ricinoleate, diethyl succinate,diisobutyl adipate, dimethyl azelate, di(n-hexyl) azelate, tri-butylphosphate, and mixtures thereof. Particularly preferred plasticizers arecitrate esters.

C. Bioactive Agents

The implants can be loaded, for example using a needle and syringe, orcoated with bioactive agents. Bioactive agents may be included in theimplants for a variety of reasons. For example, bioactive agents may beincluded in order to improve tissue in-growth into the implant, toimprove tissue maturation, to provide for the delivery of an activeagent, to improve wettability of the implant, to prevent infection, andto improve cell attachment. The bioactive agents may also beincorporated into the structure of the implant.

The implants may contain cellular adhesion factors, including celladhesion polypeptides. As used herein, the term “cell adhesionpolypeptides” refers to compounds having at least two amino acids permolecule that are capable of binding cells via cell surface molecules.The cell adhesion polypeptides include any of the proteins of theextracellular matrix which are known to play a role in cell adhesion,including fibronectin, vitronectin, laminin, elastin, fibrinogen,collagen types I, II, and V, as well as synthetic peptides with similarcell adhesion properties. The cell adhesion polypeptides also includepeptides derived from any of the aforementioned proteins, includingfragments or sequences containing the binding domains.

The implants can incorporate wetting agents designed to improve thewettability of the surfaces of the implant structures to allow fluids tobe easily adsorbed onto the implant surfaces, and to promote cellattachment and or modify the water contact angle of the implant surface.Examples of wetting agents include polymers of ethylene oxide andpropylene oxide, such as polyethylene oxide, polypropylene oxide, orcopolymers of these, such as PLURONICS®. Other suitable wetting agentsinclude surfactants or emulsifiers.

The implants can contain gels, hydrogels or living hydrogel hybrids tofurther improve wetting properties and to promote cellular growththroughout the thickness of the scaffold. Hydrogel hybrids consist ofliving cells encapsulated in a biocompatible hydrogel like gelatin,methacrylated gelatin (GelMa), silk gels, and hyaluronic acid (HA) gels.

The implants can contain active agents designed to stimulate cellin-growth, including growth factors, cellular differentiating factors,cellular recruiting factors, cell receptors, cell-binding factors, cellsignaling molecules, such as cytokines, and molecules to promote cellmigration, cell division, cell proliferation and extracellular matrixdeposition. Such active agents include fibroblast growth factor (FGF),transforming growth factor (TGF), platelet derived growth factor (PDGF),epidermal growth factor (EGF), granulocyte-macrophage colony stimulationfactor (GMCSF), vascular endothelial growth factor (VEGF), insulin-likegrowth factor (IGF), hepatocyte growth factor (HGF), interleukin-1-B(IL-1 B), interleukin-8 (IL-8), and nerve growth factor (NGF), andcombinations thereof.

Other bioactive agents that can be incorporated in the implants includeantimicrobial agents, in particular antibiotics, disinfectants,oncological agents, anti-scarring agents, anti-inflammatory agents,anesthetics, small molecule drugs, anti-angiogenic factors andpro-angiogenic factors, immunomodulatory agents, and blood clottingagents. The bioactive agents may be proteins such as collagen andantibodies, peptides, polysaccharides such as chitosan, alginate,hyaluronic acid and derivatives thereof, nucleic acid molecules, smallmolecular weight compounds such as steroids, inorganic materials such ashydroxyapatite, or complex mixtures such as platelet rich plasma.Suitable antimicrobial agents include: bacitracin, biguanide,trichlosan, gentamicin, minocycline, rifampin, vancomycin,cephalosporins, copper, zinc, silver, and gold. Nucleic acid moleculesmay include DNA, RNA, siRNA, miRNA, antisense or aptamers.

The implants may also contain allograft material and xenograft,materials, including acellular dermal matrix material and smallintestinal submucosa (SIS).

In yet another preferred embodiment, the implants may incorporatesystems for the controlled release of the therapeutic or prophylacticagents.

D. Microporous Layers

Microporous layers suitable for making the outer layers of the implantare preferably non-woven and may be produced, for example, by spunlaying, solution spinning, including dry spinning, centrifugal spinningand electro-spinning, and melt blowing. The microporous layers haveaverage pore size diameters that are less than ten microns (10 μm). Themicroporous layers may be produced from the polymers listed in SectionII.A. The microporous layers are preferably made from resorbablepolymers.

A suitable equipment set up for preparing spunlaid microfiber outerlayers for the implant includes an extruder, metering pump, dieassembly, spinning zone, fiber drawing and deposition system, and acollecting belt, bonding zone and winder (Lim H., A review of spun bondprocess, JTATM, 6:1-13, (2010)). The spunlaid microfiber outer layersmay be produced by conveying polymer extrudate via a filter and meteringpump to the die assembly, and extruding the polymer through spinneretholes. This process may be accomplished by melt spinning, dry spinningor wet spinning, but melt spinning is preferred. A preferred spinneretfor melt spinning has 40-22.0 nozzles with individual nozzle diametersranging from 1.20 to 160 microns. The extruded filaments exiting thespinneret are preferably quenched, for example using cool air, and arethen attenuated by feeding the filaments into a tapered conduit usingpreferably high velocity air. In alternative embodiments, the filamentsmay be attenuated using take-up rolls or with electrostatic methods.After attenuation, the filaments are collected on a moving belt to forma web of microporous fibers, preferably using a vacuum to aidcollection. Prior to collection on the belt, the filaments may beseparated using mechanical force, aerodynamic force, or electrostaticcharge using processes such as mechanical oscillation, electrostaticcharging, slot attenuators, air foils, full-width draw rolls andcentrifugal foaming. The filaments in the web may then be bonded, forexample, by hydroentangling, thermal or chemical means, or by needlepunching. A particularly preferred method of bonding the collected webis point-thermal bonding which bonds small regions of the collected webusing temperature and pressure to fuse fibers, and provides a flexiblespunlaid microfiber structure suitable for use as the outer layer of theimplant. The collected web may also be point bonded using ultrasonicspot welding, for example, by placing an ultrasonic horn over acalendaring roll with nips to create point bonds. Prior to bonding, thecollected web may, if desired, be calendered using calendering rolls.

In a preferred embodiment, spunlaid layers suitable for use in therhinoplasty implants are made from P4HB and copolymers thereof. Suitablespunlaid P4HB (weight average molecular weight of 50 kDa to 600 kDa) maybe produced using extrusion temperatures of 60° C. to 250° C., morepreferably 80° C. to 230° C., and even more preferably maximum extrusiontemperatures of 210-230° C. At these temperatures, it is possible tocollect P4HB spunlaid wherein the spunlaid consists of a loose networkof P4HB fibers with some slight fiber-to-fiber surface bonding due tothe surface stickiness of the P4HB fibers when deposited on thecollecting belt. Increased fiber-to-fiber bonding may be achieved usinga vacuum system with an air flow rate ranging from between 40 and 220 cuft/min (1.13-6.23 m³/min).

Dry spun microfiber outer layers suitable for making the implants may beproduced from a polymer solution by pumping the solution through aspinneret with numerous holes. A suitable equipment set up comprises asource of compressed gas, preferably air, a regulator to control the gaspressure, an inline heater to control compressed air temperature, a pumpdrive to control the injection rate of the polymer solution, a spinneretwith multiple holes through which the polymer solution is pumped, and acollector, preferably a collector that can rotate. The microfiber layersare produced by dissolving the polymer in a volatile solvent and pumpingthe polymer solution through a spinneret, allowing the solvent time toevaporate so that fibers solidify from the solution and can be collectedas a micro-fibrous nonwoven. Properties of the dry spun nonwoven may beoptimized by controlling the concentration of the polymer in thesolution, the solvent type, the weight average molecular weight of thepolymer, type of polymer, gas pressure, the distance between thespinneret and the collector, and the movement of the collector, if any.

In a preferred embodiment, dry spun layers suitable for use in theimplants are made from P4HB and copolymers thereof. A suitable dry spunlayer of micro-fibrous nonwoven for preparing an implant may be preparedby dissolving P4HB or copolymer thereof (weight average molecular weightfrom 50 kDa to 1,200 kDa) in chloroform, spinning the solution through aspinneret, and collecting the dry spun nonwoven. Further details ofpreparing suitable dry spun nonwoven made from P4HB and copolymersthereof for preparing the implants is described in US Patent ApplicationNo. 20120150285 to Cahil et al.

A suitable equipment set up for preparing electrospun microfiber outerlayers for the implant comprises a reservoir of polymer solution, a pumpfor the polymer solution, a spinneret with numerous holes connected to ahigh voltage direct current, and a grounded collector plate. To preparesuitable electrospun microfiber layers, the polymer is dissolved in asolvent, the polymer solut pumped through the spinneret preferably undera constant pressure and flow rate, and the emerging polymer solution ischarged by the electric field to form a jet of polymer materialsolution. As the charged jet of polymer moves towards the collectorplate, the solvent is evaporated, and electrospun fiber is deposited atthe collector plate to form a nonwoven microporous structure.

In a preferred embodiment, electrospun layers suitable for use in theimplants are made from P4HB and copolymers thereof. A suitableelectrospun layer of micro-fibrous nonwoven for preparing an implant maybe prepared by dissolving P4HB or copolymer thereof (weight averagemolecular weight from 50 kDa to 1,200 kDa) in a solvent, for examplechloroform, and pumping the polymer solution through a spinneretconnected to a high voltage direct current so that charged jets ofpolymer (P4HB or copolymer thereof) exit the spinneret and a nonwoven isformed at a collector plate. The concentration of the polymer in thesolvent is preferably 1 to 30 wt %, more preferably 5 to 10 wt %.Preferred solvents include methylene chloride, chloroform,dichloroethane, tetrachloroethane, trichloroethane, dibromethane,bromoform, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane,1,1,1,3,3,3-hexafluoroisopropanol, toluene, xylene, dimethylformamide,dimethylsulfoxide, and mixtures thereof. Particularly preferred voltagesfor forming the electrospun nonwoven are 3-100 kV, more preferably 5-30kV. The distance between the spinneret and the collector plate willdepend upon the charge, spinneret dimensions, ejection volume, andpolymer concentration. A distance of 5-30 cm is normally suitable whenthe electrostatic potential is close to 5-30 kV. A relative humidity of20-80% is preferred, more preferably 30-70%. Further details ofpreparing suitable electrospun nonwoven from P4HB and copolymers thereoffor preparing the implants is described in US Patent Application No.20140277572 to Martin et al.

A particular advantage of using solvent-based processes such as dryspinning, centrifugal spinning, and electrospinning to prepare nonwovensof P4HB and copolymers thereof suitable for preparing the implants isthat the nonwovens can be prepared with minimal loss of polymer weightaverage molecular weight. Typically, the loss of weight averagemolecular weight is less than 20%, more preferably between 0 and 10%.

Melt blown nonwoven suitable for preparing the implant may be preparedusing high velocity air to blow hot extruded polymer from a die tip ontoa conveyor or other collecting screen. A suitable equipment set up forpreparing melt blown microfiber outer layers for the implant includes anextruder, metering pump, die assembly, hot air blower, and a collector.To prepare the melt blown nonwoven, molten polymer is conveyed to a meltblowing die using a screw extruder where it is extruded through manyholes to create multiple polymer filaments. A stream of hot air is usedto blow and attenuate the polymer filaments, and accelerate them towardsthe collector. At the collector plate, the polymer filaments may fuse ifthe filaments are still molten, or not fuse if the filaments havesolidified very quickly after exiting the melt blowing die.

In a preferred embodiment, melt spun layers suitable for use in theimplants are made from P4HB and copolymers thereof. A suitable melt spunlayer of micro-fibrous P4HB nonwoven for preparing an implant may beprepared by feeding P4HB polymer (weight average molecular weight from50 kDa to 600 kDa) into an extruder with a temperature range of 60-275°C., more preferably 80-240° C. The molten polymer is then fed into amelt-blowing die where the polymer is extruded through a spinneret withmultiple holes, preferably on the order of 10-100 holes per inch. Theextruded polymer filaments are then blown to a collector, preferably amoving collector, by heated high velocity air where the nonwoven isformed. The distance between the melt-blowing die and the collector ispreferably 3-36 inches, and more preferably 8-27 inches. In a preferredmethod, the high velocity air is heated to 100-300° C., and morepreferably to 180-240° C. The thickness of the nonwoven, density andfiber sizes can be controlled by varying a number of parameters,including, but not limited to, polymer weight average molecular weight,die configuration, hole spacing in the spinneret, number and size of theholes in the spinneret, temperature of the high velocity air, quenchingtemperature, distance between the die and collector, and the speed oftravel of a moving collector screen. Further details of producingsuitable melt blown nonwoven from P4HB and copolymers thereof forpreparing the implants is described in US Patent Application No.20090162276 to Martin et al.

In a preferred embodiment, the microporous nonwoven layers produced, forexample, by spun laying, dry spinning, electrospinning and melt blowing,optionally from P4HB or copolymers thereof, have fibers with averagediameters in the range of 100 nm to 20 μm, and more preferably 1 μm to10 μm. In another preferred embodiment, the microporous nonwoven layersproduced, for example, by spun laying, dry spinning, electrospinning andmelt blowing, optionally from P4HB or copolymers thereof, have averagepore size diameters of less than 10 μm, and more preferably 0.5 μm to 10μm. In a further embodiment, the microporous nonwoven layers produced,for example, by spun laying, dry spinning, electrospinning and meltblowing, optionally from P4HB or copolymers thereof, have a thicknessbetween 5 μm and 100 μm.

It is generally preferred that the microporous layers of the implant aremade from one or more resorbable polymers, and degrade in 1 to 6 months.Implants can be made, for example, from polyglycolic acid if fastresorption of the microporous layers is required. Implants with somewhatslower degrading microporous :layers can be made, for example, fromcopolymers of glycolic and lactic acid, or from polydioxanone. In aparticularly preferred embodiment, the microporous layers of the implantcan be made from unoriented P4HB fibers. The rate of degradation of theP4HB fibers may be further controlled by selecting the weight averagemolecular weight of the polymer. When slower degrading implants arerequired, P4HB with weight average molecular weight of 350 to 600 kDacan be used, and P4HB with weight average molecular weight of 50 to 349kDa can be used when faster degradation is required. Incorporatingsmaller diameter P4HB fibers into the microporous layer will also resultin more rapid degradation of the implant. For example, unoriented P4HBfibers with diameters of 1 to 100 μm may degrade in 1-3 months whereasunoriented P4HB fibers with diameters over 100 μm may degrade in 3-6months or more. In a preferred embodiment, the microporous layers haveP4HB fibers with one or more of the following properties: (i) weightaverage molecular weight between 50 and 349 kDa; (ii) fiber diametersbetween 1 to 100 μm; and (iii) no orientation or partial orientation,preferably so the fibers have an elongation to break between 50% and1,000%. For reference purposes, an unoriented P4HB fiber has anelongation to break of 1,000%. In another embodiment, the microporouslayers have P4HB fibers with one or more of the following properties:(i) weight average molecular weight between 350 and 600 kDa; (ii) fiberdiameters between 101 and 250 μm; and (iii) unoriented or partiallyoriented P4HB fibers, preferably P4HB fibers with an elongation to breakbetween 50% and 1,000%.

E. Macroporous Filler

The implant may optionally comprise one or more fibrous structures,including layers such as a nonwoven, or loose fiber structure, that ismacroporous inside the finable reservoir of the implant. Suitablemacroporous fiber structures can be produced, for example, by knitting,melt spinning or wet spinning fiber, including production of macroporousnonwoven fiber structures by spun laying and melt blowing. Aparticularly preferred method of producing the macroporous fiber filleris by spun laying.

The macroporous filler may be produced from the polymers listed inSection II.A. The macroporous fillers are preferably made fromresorbable polymers.

In a preferred embodiment, the average fiber diameters of themacroporous fibers that can be used inside the finable reservoir of theimplant, optionally made from P4HB and copolymers thereof, are 10 μm to250 μm, and more preferably 20 μm to 50 μm. In another preferredembodiment, the average pore size diameters of the macroporous fiberstructures, or macroporous inner layers, that can be used inside thefillable reservoir of the implant, optionally made from P4HB andcopolymers thereof, are 75 μm to 5 mm, and more preferably 100 μm to 500μm. In one embodiment, suitable spunlaid macroporous fiber may beproduced from P4HB (weight average molecular weight of 50 kDa to 600kDa) using extrusion temperatures of 60° C. to 250 more preferably 80 to230° C., and even more preferably maximum extrusion temperatures of210-230 ° C., and a vacuum system with an air flow rate ranging frombetween 40 and 22.0 cu ft/min (1.13-6.23 m³/min). In a preferredembodiment, the P4HB spunlaid macroporous fiber structure is prepared bycooling the extruded filaments at a temperature between 4° C. and 30°C., more preferably from 15° C. to 25° C. to allow fiber surfacecrystallization and minimize fiber-to-fiber melt adhesion. In anotherpreferred embodiment, the P4HB spunlaid macroporous fiber may be heatedusing a post-collection air stream at a temperature between 30° C. and58° C., more preferably between 42° C. and 52  C., in order to softenthe P4HB fibers and make them tacky to obtain improved cohesion of thefibers in the spunlaid. In a preferred embodiment, the P4HB macroporousfibrous structure has one or more of the following properties: (i)unoriented fibers or partially oriented fibers with elongation to breakvalues between 50 and 1,000%; (ii) average fiber diameters of 10 μm to250 μm; (iii) polymer fiber weight average molecular weight from 50 kDato 600 kDa, more preferably 50 kDa to 350 kDa; and (iv) average poresize of >75 microns to 5 mm.

III. Methods of Manufacturing Implants with Fellable Reservoirs

A variety of methods can be used to manufacture the implants.

In one embodiment, an implant with a fillable reservoir is prepared fromtwo microporous layers by placing one layer on top of the other layer,and sealing their edges together as shown in FIG. 1 . The edges may besealed together to form a fillable reservoir between the microporouslayers, for example, by using a calendering system wherein a heated baror a roll of heated bars is pressed against the edges of the twomicroporous layers in order to seal them together. In anotheralternative method, the edges of the two microporous layers may besealed together using ultrasonic welding bars. If desired, the implantmay comprise additional microporous layers, and comprise multiplefinable reservoirs as shown in FIG. 2 . These implants may also beprepared by stacking microporous layers on top of each other, andsealing their edges together as shown in FIG. 2 . As described above,the microporous layers may be prepared, for example, by spun laying, dryspinning, electro-spinning, and melt blowing. The microporous layers maybe made from the same material or from different materials, or by thesame technique or different techniques. For example, microporous layersmade from fast and slow resorbing polymers can be incorporated into theimplant. Or, a microporous layer coated with a bioactive substance maybe combined with other microporous layers that do not contain bioactivesubstances. Or, for example, a microporous layer made by spun laying canbe combined in an implant with a microporous layer made with a dry spun,melt blown or electrospun microporous layer, or any combinations of spunlaid, dry spun, electrospun and melt spun layers combined in an implant.A particularly preferred polymer for preparing the implants shown inFIGS. 1 and 2 is P4HB and copolymers thereof.

In another embodiment, an implant with one or more finable reservoirsmay be prepared by wrapping a microporous layer around a flat substratethat has been placed on a mandrel as shown in FIG. 3 . Parallel layersof the microporous substrate are formed as the mandrel is rotated, asshown in the cross-sectional view of FIG. 3 . By sealing the edges ofthe microporous layer, an implant is formed with a reservoir between thelayers of the microporous nonwoven. The distance between the microporouslayers, which in turn determines the capacity of the reservoir, can becontrolled by applying more or less tension to the microporous layerwhile it is being rotated about the flat substrate. Preferably, themicroporous layers are prevented from wrinkling, and structural failure,as they are wrapped around the flat substrate by keeping them flat.Driving rollers and sprockets can be used for this purpose. In apreferred embodiment, a tension of 10-200 cN/cm is applied to themicroporous layer during wrapping. A particularly preferred polymer forpreparing the implant shown in FIG. 3 is P4HB and copolymers thereof.

The implants, when used in rhinoplasty procedures, should preferablyhave a tillable reservoir or reservoirs with a capacity of between 0.1and 3 cc, more preferably at least 0.2 cc, and even more preferablybetween 0.2 cc and 3 cc. The implants, when used in ear reconstructionshould preferably have a tillable reservoir or reservoirs with acapacity of the reservoir or reservoirs between 0.1 and 2 cc. Theimplants, when used in breast reconstruction or soft tissue repairshould preferably have a fillable reservoir or reservoirs with acapacity of the reservoir or reservoirs between 10 and 150 cc. Theimplants may be designed and constructed so that the reservoir orreservoirs expand upon filling.

In a preferred embodiment, the implants further comprise fiber fillerthat forms a macroporous structure, including a nonwoven. Themacroporous fiber structure can help provide a reservoir foraugmentation materials, particularly fluid augmentation materials,including microfat, fat, fat extracts, collagen, DCF, gels, hydrogels,cells, stem cells, as well as bioactive agents. Preferably, themacroporous fiber filler structure helps the implant when used in arhinoplasty procedure retain up to one cc of fluid volume. In apreferred embodiment, the ratio of the volume of the implant occupied bythe microporous outer layers, and optionally the fibers of themacroporous structure, to the total volume of the implant is between0.05 and 20%, and more preferably between 0.1-2%.

In another embodiment, the implants may comprise one or more macroporesin the microporous layers. For example, the implants shown in FIGS. 1-3may contain one or more macropores. Macropores are desirable in implantsthat comprise thicker microporous layers, and in particular when theoverall thickness of the implant is 0.4 mm or more. Placing rnacroporesin thicker microporous layers (e.g. of 0.4 mm of more) allows bettercell ingrowth by facilitating diffusion of oxygen, nutrients, and wasteproducts to support and maintain viable tissue. The size of the one ormore macropores may range from 0.0045 mm² to 5 mm², and is morepreferably between 0.25 mm² and 4 mm². Preferably, the macropores have aminimum diameter of 75 μm. In the event the implant further comprisesthermal bonding points, the macropores are preferably located at least 5mm away from the thermal bonding points. The macropores may have anyshape, such as circular, triangular and diamond shapes, and the same ordifferent shapes within an implant. A circular shape is preferred tomaintain better mechanical integrity. FIG. 4 shows an example of therhinoplasty implant (shown in FIG. 2 ) that has been perforated withmacropores. The macropores may be inserted in the microporous layers byany suitable means, including mechanical punching and cutting with alaser.

In a further embodiment, an implant with a fillable reservoir can beprepared by alternating layers of microporous nonwoven with layers ofmacroporous fiber structure as shown in FIG. 5 , and sealing the edgesof the layers as described above. In this embodiment, the implant has atleast one layer of macroporous fiber structure wrapped and sealed by anouter layer of a microporous nonwoven membrane. In a preferredembodiment, the implant comprises 2 to 20 microporous layers and 1 to 19macroporous fiber layers that alternate with the microporous layers,with the exterior of the implant consisting of a microporous layer.

In a particularly desired embodiment, the implants are thermally pointbonded, Thermal point-bonding of the implants increases the strength ofthe implant, and can prevent delamination of layers incorporated intothe implant. The implants are thermally point-bonded by applying heatand pressure at discrete points, for a period of time, and preferablyusing a calender. A preferred method to thermally point-bond an implantusing an engraved calender roll and a smooth calender roll is shown inFIG. 6 . The depth and dimensions (e.g. diameter or width) of thepoint-bonds, and the distance between point-bonds can be controlled byvarying the positions and sizes of the protrusions engraved on thecalender roll, as well as process conditions such as roller diameter,pressure in the roller gap, speed of the structure to be point-bondedthrough the calendering rolls, and the roller temperature, as shown inFIG. 6 . In a particularly preferred embodiment, the implant is madefrom P4HB or copolymer thereof, and is thermally point-bonded.

A cross-sectional view showing in more detail a fillable reservoir of animplant formed by the process of thermal point-bonding is shown in FIG.7 . The implant comprises an external outer microporous nonwoven layerand a macroporous inner layer of fiber, and is part of an interconnectednetwork of unit cells comprising a microporous outer layer and amacroporous fiber inner layer. FIG. 8 shows the manufacture of the unitcell shown in FIG. 7 (see area “A”). FIG. 9 shows the design of animplant with an interconnected network of unit cells creating a fillablereservoir that can be prepared by thermal point-bonding. The implantcomprises an external microporous layer, and optionally can be filledwith loose fibrous material forming a macroporous structure. The implantmay be cut and shaped to size. In a particularly preferred embodiment,the implant is prepared from P4HB or copolymer thereof.

An example of a P4HB implant that has been thermally point-bonded withthe pattern shown in FIG. 10 is shown in FIG. 11 . The implant comprisesdry spun and spunlaid layers that have been thermally point-bonded. FIG.11(a) shows the point-bonded implant with a finable reservoir afterthermal point-bonding. FIG. 11(b) is a magnified picture of the implantshowing the square pattern of thermal point bonds in the P4HB implant.FIG. 11(c) shows a 1.5 cm×3.5 cm rhinoplasty implant prepared from theimplant of FIG. 11(a) wherein the implant's finable reservoir has beenfilled with 0.8 cc of human microfat using a needle and syringe.

The minimum tensile strength of the implant should be high enough tomaintain the integrity of the implant during preparation of the implantand placement at the implantation site. The implant should havesufficient strength to prevent it from unraveling and fraying, yet beeasy for the surgeon to cut. In an embodiment, the implants prepared asdescribed herein should have a minimum tensile strength of 0.5 N/cm, anda maximum tensile strength of 50 N/cm. In another embodiment, theimplant should have a minimum burst strength of 1 N/cm², and a maximumburst strength of 40 N/cm². In a preferred embodiment, the implantcomprises P4HB or copolymer thereof, and has one or more of thefollowing properties: a tensile strength between 1 N/cm and 20 N/cm, asuture pullout strength of 0.1 to 100 N, and more preferably 1 to 25 N,and a burst strength between 2 N/cm² and 25 N/cm².

IV. Methods of Implanting

The implants may be used in rhinoplasty procedures, for example to (i)improve aesthetic appearance of the patient's nose; (ii) restorestructure and shape following trauma; (iii) correct abnormalities of thenose; and (iv) correct functional problems of the nasal passage toimprove breathing. The implants may be used alone or in combination withother techniques to alter underlying nasal structures such as bone,cartilage, ligaments and soft tissue. The implants may be used to createor preserve certain proportions between various parts of the nose andface in order to restore or maintain functionality, remediate structuralissues, and address aesthetic factors. The implants may be used in open,closed or minimally invasive rhinoplasty procedures, and may be used inprimary or secondary rhinoplasty procedures. The implants may be cut andshaped for specific procedures, and are preferably fixated in place, forexample, using sutures and more preferably absorbable sutures.

Preferably, the reservoirs of the implants are filled with microfat,fat, fat extracts, cells, diced cartilage, or other biological materialprior to implantation, but the implants can be used without fillingtheir reservoirs. Augmentation materials used to fill the reservoirs maybe autografts, allografts, xenografts or other biological or syntheticmaterials. Particularly preferred materials are microfat and DCF. Anysuitable method can be used to fill the reservoir of the implant;however, a preferred method is to use a syringe and needle.

In an embodiment, the implants may be used to augment the nose dorsum(build up the bridge of the nose). The implants may be used to treatpatients with collapsed or flat noses, or to change the appearance of arelatively low bridge, common in certain ethnic groups, to a moreprojected, pronounced or “Western” profile. For these procedures, it ispreferable, but not essential that the size of the implant is 1.5 cm×3.0cm. In a preferred method to augment the dorsum, the implant is filledwith diced cartilage fascia (DCF) or other augmentation material such asmicrofat. DCF may be obtained, for example, from cartilage of the rib,ear, or septum. The cartilage is chopped into very small pieces,typically about 0.5 to 1 mm cubes. To augment the dorsum, the DCF isplaced inside the fillable reservoir of the implant, and the implant isinserted onto the dorsum. The implant may be secured at the implantationsite using sutures or by another suitable fixation method.

In other embodiments, the implant may be used to modify the nasal tip,for example, to improve nasal tip projection. The implant may be graftedonto the intermediate crura to accentuate the nasal tip, or be used as acolumellar strut, including a septal extension graft, for example, tolengthen a short nose. In another embodiment, the implant may be used asa caudal septal extension graft, for example, to support the nasal tip,prevent postoperative loss of tip projection, or set nasal length. Infurther embodiments, the implant may be fixated to alar cartilage, forexample, as a shield graft, or used as a spreader graft or middle vaultaugmentation graft, for example, to increase middle vault width, improvesymmetry, increase the airway or straighten the dorsum septum. Theimplant may also be used to lengthen the nose, or provide thatappearance, for example by placing implants on the caudal aspect of thealar domes.

Although it is intended that a significant use of the implants will bein rhinoplasty procedures, the implants may be used in other surgicalprocedures, including other plastic surgery procedures and generalsurgery procedures. For example, the implants may be used inreconstruction of the ear. In this case, it is desirable that the sizeof the implant is 3 cm×6 cm. The implants may also be used as asubstitute for a TRAM (transverse rectus abdominis myocutaneous) flap,for example, to reconstruct a breast or other tissue. In this case, thesize of the implant is preferably 10 cm×20 cm. The implants may also beplaced subcutaneously in the upper pole of the breast to create volume,

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLE 1 Manufacture of an Implant with a Fillable Reservoir andMacroporous Fiber Filler

Microporous P4HB dry spun (Mw=250 kDa) was prepared by solution spinningan 8% solution of P4HB in chloroform through a 1.0 mm annular spinneret(1.1 mm inner diameter and 2.1 mm outer diameter) to yield a dry spunnonwoven with a thickness of 162 microns, density of 4.5 mg/cm², andfiber diameter of 3.9±4.3 μm. A macroporous spunlaid P4HB nonwoven wasprepared by melt extrusion of P4HB (Mw=460 kDa) using a maximumtemperature of 247° C., through a die with spinneret hole diameters of150 μm and temperature of 20-25° C., attenuating the filaments, andcollecting the P4HB filaments on a moving belt. The formed macroporousspunlaid structure had a fiber size ranging from 19 to 64 μm, arealdensity of 18±4 mg/cm² an average thickness of 1.6±0.4 mm, and anaverage pore size (diameter) of 413±219 μm. The implant was then formedby thermal point bonding of a sandwich structure comprising outer layersof P4HB microporous dry spun with an inner layer of loose macroporousspunlaid P4HB fibers at a temperature of 63° C. The bonding pointgeometry used was mm squares. Bonding points were in a diamond patternand were 6.5 mm apart. Prior to implantation, the implant was filledwith 0.8 cc of micro fat (extracted from human fat by centrifugation)using an 18-gauge needle and 1 cc syringe.

EXAMPLE 2 Manufacture of an Implant with a Fillable Reservoir, NoMacroporous Fiber Filler Structure, and Laser Cut Macropores

Eight layers of the microporous P4HB dry spun prepared in Example 1 werestacked on top of each other, and thermally point bonded as described inExample 1 (with the same pattern). A laser was then used to cut diamondpatterned macropores in the implant that had a size of 1 mm×2 mm.

EXAMPLE 3 Manufacture of an Implantable Fillable Reservoir Made ofNonwoven Felt Sandwiched Between Two Layers of Melt-Blown

Needle punched P4HB multifilament was formed into a nonwoven felt of 2-4mm thickness and placed between two P4HB melt-blown layers. Themelt-blown was prepared using the equipment set up shown in FIG. 12 ,and conditions shown in Table 1, from P4HB pellets which were driedunder vacuum overnight to less than 0.01% (w/w) water content. Theequipment used for melt blowing consisted of a 6″ melt-blowing die fedby a 1″ single screw extruder. The die was configured with 120 holes of0.010″ diameter, 3:1 L/D. The die tip was set back 0.060″ from the faceof the die and had a 0.060″ air gap. A melt temperature of about 230°C., and air temperature of 230° C. provided a good web of P4HB fibers.The speed of the belt collector was varied to collect P4HB melt-blownnon-wovens of various thicknesses as shown in Table 2. An implant with afinable reservoir was prepared from a composite structure of the needlepunched NUB nonwoven felt and the melt-blown by quilt spot bonding thelayers using thermal energy, and the edges of the sandwiched layers werethermally sealed.

TABLE 1 Conditions for melt-blowing P4HB Polymer prepared in Example 3Extruder Ambient Die Attenuation Air Zone 1 Zone 2 Zone 3 ConnectorSpeed Air Temp Zone 2 Zone 3 Zone 4 Press. Press. Temp. DCD Deg C Deg CDeg C Deg C RPM Deg C Deg C Deg C Deg C PSI PSI Deg C mm 144.7 202.9 234229.7 2 33.5 248.3 228.4 238.5 700 3 230 630

TABLE 2 Properties of P4HB melt-blown prepared in Example 3 SampleThickness, Unit Weight, Ball Burst, Roll # Sample # mm gm/m2 KGF 1 100.166 64.6 2.9 2 5 0.114 38.5 1.5

EXAMPLE 4 Manufacture of an Implantable Finable Reservoir Made of aKnitted P4HB Mesh Sandwiched Between Two Layers of P4HB Macroporous Felt

Microporous P4HB felt was made by needle punching a loose web ofunoriented P4HB fibers (Mw=300 kDa) with a diameter range of 50 to 165microns. Needle punching was performed using 11 needles per inch toproduce a felt with an average thickness of 1.2 mm, and an average arealdensity of 280 g/m². The average pore size of the needle punched P4HBfelt was 120 microns. A macroporous P4HB layer was produced by knittingsize 5-0 oriented P4HB monofilaments (Mw=34(3 kDa) in a diamond patternwith an average pore size of 320 microns and an average areal density of132 g/m². The diamond knitted mesh was sandwiched between two layers ofthe P4HB needle punched felt, and the layered structure was then placedover a 5 cm×5 cm aluminum anvil with a diamond welding pattern. Thecomposite was welded with round bonding points having a 0.13 mmdiameter, placed 6.35 mm deep and 6.35 mm apart using a 3-inch circularhorn driven and bonded using a Branson 2000X ultrasonic unit. Theultrasonic welding energy used was 10 Joules, with a hold time of 0.3seconds, and an amplitude of 80% and a pressure of 30 psi (206 kPa).

EXAMPLE 5 Manufacture of an Implantable Fillable Reservoir Made ofMicroporous and Macroporous Layers for Use as a Meniscus Plug

An implant with a finable reservoir was prepared by sandwiching amacroporous layer of P4HB spunlaid between outer layers of microporousP4HB dryspun, and thermally point bonding the construct to formbarrel-like reservoirs as shown in FIG. 13 . The layers were thermallypoint bonded at 63° C. for 15 seconds to produce the barrel-likereservoirs with an average diameter of 4 mm and an average height of 5mm as shown in FIG. 13 . A square bonding pattern with 5 mm spacing and1 mm circular point bonds was used. Prior to implantation, the implantwas filled with 0.3 cc of diced cartilage with average chunk size of 0.5mm using a 12-gauge needle and 1 cc syringe. The filled construct wasthen cut to size using a 6 mm round punch with the cartilage-loadedreservoir at the center.

EXAMPLE 6 Manufacture of an Implantable Fillable Reservoir Made of aP4HB Hollow Braid Coated with a Thin Microporous Layer

An implant with a tillable reservoir was prepared by braiding 6-0monofilament P4HB fibers (average fiber diameter of 100 μm) using a12-carrier braiding machine, 1×1 pattern, diamond pore shape, and an 8mm diameter round core. The braid along with the core was cut in 12 inlong (30.48 cm) sections placed on a wire mandrel and rotated at 12 rpm.The same dry spinning setup and parameters described in Example 1 wereused to deposit a thin layer (average thickness of 84 μm) of microporousP4HB dry spun over the rotating braid. Upon completion, the inner corewas removed from the coated braid, and the coated braid was sealed andcut into 4 cm long sections using a 1 centimeter wide impulse sealer anda pair of scissors. The resulting structure was a barrel-like reservoirwith sealed top and bottom ends. The sides of the reservoir consisted ofa loose macroporous braided inner layer with an average 0.9 mm pore sizeand an outer macroporous layer composed of dry spun P4HB. The reservoircan be filled with about 2 cc of diced cartilage using a 10 gaugesyringe and needle.

Modifications and variations of the methods and compositions will beapparent from the foregoing detailed description and are intended tocome within the scope of the appended claims.

1-32. (canceled)
 33. An implant comprising: a fillable reservoir with amicroporous outer layer, the microporous outer layer including aplurality of micropores; and a macropore in the microporous outer layer,wherein the macropore has a size between 0.0045 mm² and 5 mm², andwherein the plurality of micropores have an average diameter of lessthan 10 μm.
 34. The implant of claim 33, further comprising a pluralityof macropores in the microporous outer layer.
 35. The implant of claim33, wherein the macropore has a size between 0.25 mm² and 4 mm².
 36. Theimplant of claim 33, further comprising a macroporous structure madefrom fibers inside the fillable reservoir.
 37. The implant of claim 33,wherein edges of the microporous outer layer are sealed.
 38. The implantof claim 33, wherein the implant is part of an interconnected network ofunit cells.
 39. The implant of claim 33, further comprising additionalmicroporous layers forming multiple fillable reservoirs.
 40. The implantof claim 39, wherein the additional microporous layers are stacked ontop of each other.
 41. The implant of claim 40, wherein edges of theadditional microporous layers are sealed together.
 42. The implant ofclaim 33, wherein the implant further comprising alternating layers ofmicroporous nonwoven with layers of microporous fiber structure.
 43. Theimplant of claim 33, wherein the implant further comprises thermalbonding points.
 44. The implant of claim 43, wherein the macropore ispositioned at least 5 mm away from the thermal bonding points.
 45. Theimplant of claim 33, wherein the macropore has a circular shape.
 46. Theimplant of claim 33, wherein the macropore has a triangular or diamondshape.
 47. The implant of claim 33, wherein the implant is made frompoly-4-hydroxybutyrate or a copolymer thereof.
 48. The implant of claim33, wherein the microporous outer layer has a thickness of 0.4 mm ormore.
 49. The implant of claim 33, wherein the microporous outer layercomprises a nonwoven membrane.
 50. The implant of claim 33, wherein themicroporous outer layer comprises an exterior of the implant.